GALC

protein-coding

galactosylceramidase, the group of Glycoside hydrolases

Gene summary

This gene encodes a lysosomal protein which hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Mutations in this gene have been associated with Krabbe disease, also known as globoid cell leukodystrophy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000153.4

Inheritance

ClinVar variants

P:431U:356B:348

Top phenotype

Krabbe disease

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr14:87,837,820-87,993,665

External References & Databases

Ensembl (ENSG00000054983)

Transcript & Mutation Effects

hg38 • Region Span ~155.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Krabbe diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009499

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Krabbe diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009499

Submitter: Myriad Women's Health

Krabbe diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009499

Submitter: PanelApp Australia

Krabbe diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009499

Submitter: ClinGen

The relationship between the GALC gene and Krabbe disease, an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of April 18, 2022. GALC encodes galactocerebrosidase (GALC), a lysosomal enzyme involved that removes galactose from galactosylceramide, a glycosphingolipid (PMID: 8281145, PMID: 1164212, PMID: 5271165). When GALC is deficient, as is the case among individuals with Krabbe disease, the enzyme acid ceramidase removes the fatty acyl chain from galactosylceramide to generate psychosine (PMID: 31527255). Psychosine is a cytotoxic glycolipid that results in loss of oligodendrocytes and Schwann cells, leading to CNS and PNS demyelination and the neurologic anomalies seen in Krabbe disease (PMID: 34449528, PMID: 31527255). The disease mechanism of Krabbe disease is loss of function. Krabbe disease was first reported in 1916 (PMID: 24137751) and the first report of biallelic variants in GALC among patients with Krabbe was published in 1994 (PMID: 8297359). Since then, at least 260 unique variants have been identified (PMID: 34449528). Both case-level (genetic) and experimental evidence support the relationship between Krabbe disease and GALC. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants, as well as larger deletions, including a recurrent 30kb deletion encompassing exons 11-17 (as reviewed in PMID: 34449528). In total, nine variants from five probands in three publications were curated (PMID: 23462331, PMID: 8786069, PMID: 20886637); although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between GALC and Krabbe disease includes the biochemical function of the gene product (the GALC enzyme) being consistent with the clinical and biochemical findings identified individuals with Krabbe disease (PMID: 8281145, PMID: 1164212, PMID: 5271165, PMID: 34449528, PMID: 31527255), the biochemical and clinical features of a mouse animal model (‘twitcher’ mouse model) homozygous for the p.W339* variant (PMID: 7417782, PMID: 8769874), and the impact of hematopoietic stem cell transplant therapy among human Krabbe patients (PMID: 15901860, PMID: 28855403). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, GALC is definitively associated with Krabbe disease. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time.

Krabbe diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009499

Submitter: Genomics England PanelApp

Krabbe diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009499

Submitter: Labcorp Genetics (formerly Invitae)

Krabbe diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009499

Submitter: G2P

Krabbe diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009499

Submitter: Natera

Clinical Genomic Database (CGD)

Krabbe diseaseAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: BMT/HSCT have been described, and in presymptomatic infants as well as older mildly-affected individuals, this treatment may improve and preserve cognitive function (ie, presymptomatic transplant has much better neurological outcomes)

Refs: 14024503; 3123790; 4773865; 1817026; 1817027; 2056315; 1891085; 8297359; 7581365; 9449482; 8940268; 9338580; 9545360; 10833326; 15901860; 16607461; 17579360; 19332366; 21070211; 20301416; 20886637; 22115770; 22704718; 23462331; 23276707; 33832819

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GALC variants in ClinVar

34 Conditions Cataloged

Galactosylceramide beta-galactosidase deficiencyTotal: 1311

not providedTotal: 303

not specifiedTotal: 118

Inborn genetic diseasesTotal: 65

GALC-related disorderTotal: 38

GALC-related disordersTotal: 15

Intellectual disabilityTotal: 6

See casesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000153.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	7 clinvar	325 clinvar	3 clinvar	336
missense	17 clinvar	125 clinvar	343 clinvar	17 clinvar	3 clinvar	505
nonsense	45 clinvar	39 clinvar	1 clinvar			85
start loss		3 clinvar	2 clinvar			5
frameshift	86 clinvar	53 clinvar	1 clinvar			140
splice donor/acceptor (+/-2bp)	14 clinvar	48 clinvar	2 clinvar			64
Total	162	269	356	342	6	1135

Highest pathogenic variant AF is 0.0037812707

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000153.4	RefSeq	NP_000144.2	17	MANE Select
ENST00000261304.7	Ensembl	ENSP00000261304.2	17	MANE Select
NM_001201401.2	RefSeq	NP_001188330.1	16	Standard
NM_001201402.2	RefSeq	NP_001188331.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Sphingolipid metabolism - Homo sapiens (human)
Sphingolipid Metabolism
Gaucher Disease
Globoid Cell Leukodystrophy

Biological Process

galactosylceramide catabolic process
glycosphingolipid metabolic process
myelination

Molecular Function

galactosylceramidase activity

Cellular Component

lysosome
lysosomal lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261304
Coding exons: 17
Length: 155846
Individuals with no LoFs: 124685
Homozygous LoFs: 0
Heterozygous LoFs: 113
Defined: 124798
p: 0.000453

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.186	365	375	0.973	0.0000193	4447
Missense (PolyPhen)		124	149.03	0.83204		1770
Synonymous	-0.0698	136	135	1.01	0.00000715	1286
Loss of Function	1.88	29	42.2	0.687	0.00000216	461

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00026	rare
Latino/Admixed American	0.00052	0.00052	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00028	0.00028	rare
Finnish	0.00047	0.00046	rare
European (Non-Finnish)	0.00050	0.00049	rare
South Asian	0.00046	0.00046	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon. {ECO:0000269|PubMed:8281145, ECO:0000269|PubMed:8399327}.;
Disease: DISEASE: Leukodystrophy, globoid cell (GLD) [MIM:245200]: An autosomal recessive disorder characterized by insufficient catabolism of several galactolipids that are important for normal myelin production. Four clinical forms are recognized. The infantile form accounts for 90% of cases. It manifests before six months of age with irritability, spasticity, arrest of motor and mental development, and bouts of temperature elevation without infection. This is followed by myoclonic jerks of arms and legs, oposthotonus, hypertonic fits, and mental regression, which progresses to a severe decerebrate condition with no voluntary movements and death from respiratory infections or cerebral hyperpyrexia before 2 years of age. Cases with later onset present with unexplained blindness, weakness and sensorimotor peripheral neuropathy, mental deterioration and death. {ECO:0000269|PubMed:10234611, ECO:0000269|PubMed:10477434, ECO:0000269|PubMed:17579360, ECO:0000269|PubMed:20886637, ECO:0000269|PubMed:23462331, ECO:0000269|PubMed:8595408, ECO:0000269|PubMed:8786069, ECO:0000269|PubMed:8940268, ECO:0000269|PubMed:9272171}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.449

Intolerance Scores

LoFtool: 0.252
RVIS EVS: 0.85
RVIS percentile EVS: 88.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.407

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High